Fentanyl is a synthetic opioid. As a result of fentanyl's clinical success and the need to more clearly define the structural requirements necessary for its μ opioid agonist efficacy, extensive efforts have been devoted to developing the structure activity relationships of the 4-anilidopiperidine class of analgetics (Borne et al., J. Med. Chem. 27:1271 (1984); Janssen, U.S. Pat. No. 3,161,644 (1964); Kudzma et al., J. Med. Chem. 32:2534 (1989); Colapret et al., J. Med. Chem. 32:968 (1989); Janssens et al., J. Med. Chem. 29:2290 (1986)). As a result of these efforts, two congeners of fentanyl, alfentanil and sufentanil, were discovered and have found clinical utility as anesthesia adjuncts. In comparison with fentanyl, alfentanil has a shorter duration of action and sufentanil has 5–10 fold greater potency.
With the emphasis in anesthetic and surgical practice focusing on shorter and outpatient surgical procedures, the need for an ultrashort acting opioid analgetic has surfaced. Although alfentanil is considered an ultrashort acting agent, its terminal half-life in humans, approximately 70–90 minutes, is longer than desired for certain procedures. The ideal ultrashort-acting analgetic should have a biological half life ranging from 1–30 minutes. In this case, rapid elimination or biotransformation of such an agent to inactive or less active products would minimize. accumulation and subsequent redistribution with prolonged or repeated administration. Furthermore, respiratory depression and muscle rigidity, two well documented μ opioid effects with agonists of high intrinsic efficacy, would be of short duration.
In order to discover an analgetic with the desired profile, the 4-anilidopiperidine structure was modified such that the metabolism could be achieved through a rapid enzymatic reaction in the blood (Feldman et al., J. Med. Chem. 34:2202 (1991)).
The two most commonly used piperidine nitrogen substituents in these analgetics are the phenethyl and 2-thienylethyl both of them being very lipophilic. The strategy of Feldman et al. involved replacing the aryl groups with a lipophilic group that would still retain the binding characteristics of the aryl groups, but upon enzymatic degradation would yield a polar group with less affinity for the μ receptor, and greater chances for rapid elimination (U.S. Pat. No. 5,019,583).
As a result of extensive testing of several of these analogs, Remifentanil has emerged as a potent opioid analgesic with an extremely short half-life (10–20 minutes) (Amin et al., J. Pharmacol. Exp. Ther. 274:34 (1995)) and has undergone successful clinical trials and is awaiting FDA approval.
The instant invention is an improved method of synthesizing 4-anilidopiperidine derivatives, especially alfentanil, sufentanil and remifentanil.
Alfentanil is a member of the series of potent fentanyl analogues. The chemical name for alfentanil is: propanamide, N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenyl-. It is also called: N-1{1-{2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl}-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide. It was first synthesized in 1976 (U.S. Pat. No. 4,167,574). Alfentanil appears to have most of the properties sought in the ideal analgesic. These are 1) reliable, dose-related analgesia, 2) rapid onset, 3) duration adaptable to clinical situation, 4) minimal cardiovascular impairment, and 5) fast, complete recovery, without hangover (Drugs of Today, volume 20(1) (1984)). The analgesic potency of alfentanil is one-quarter that of fentanyl. The duration of its action is one third that of an equianalgesic dose of fentanyl and is clearly dose-related. Its depressant effects on respiratory rate and alveolar ventilation are also of shorter duration than those of fentanyl, and in most cases the analgesic effect lasts longer than the respiratory depression. The onset of action of alfentanil is 4 times more rapid than that of an equianalgesic dose of fentanyl and the peak analgesic and respiratory depressant effects occur within 90 seconds of administration.
The acute intravenous (i.v.) toxicity of alfentanil was studied in rats and an LD50 of 47.5 mg/kg was established whereas fentanyl's LD50 was 3.05 mg/kg i.v.
In man, the mean elimination half-lives of alfentanil and fentanyl were found to be 1.63 and 3.09 hours, respectively (Bower and Hull, Brit. J Anaesth. 54:871–887 (1982)). Plasma protein binding of alfentanil was significantly greater than that for fentanyl, and alfentanil did not bind to erythrocytes. It is also less lipid soluble than fentanyl and has a much lower volume of distribution relative to fentanyl (0.86 vs. 4.21 per kilogram). Alfentanil appears to be unique among the opioids in having a small apparent volume of distribution and low clearance (Stanski and Hug, Anesthesiol. 57:435–438 (1982)).
The rapid onset and short duration of action makes alfentanil particularly suitable for surgical procedures of short duration, such as day case surgery or where a rapid suppression of reflex responses is required. Cardiovascular parameters remain stable and recovery is remarkably fast and complete (Sinclair and Cooper, Anaesthesia 38:435–437 (1983)).
Although alfentanil is considered a short-acting analgesic, especially suited for brief surgical procedures, the drug can also be used for longer operations. In this case, a bolus of alfentanil must be followed by an infusion at a rate sufficient to compensate for the disappearance of the drug due to redistribution and elimination (Noorduin et al., Drug Dev. Res. 8:347–352 (1986)). In view of its brief but controllable action, alfentanil may prove of particular value in patients undergoing acutely painful but transient procedures such as reduction of fractures, dilatation and curettage, as well as in painful dental conditions.
Sufentanil citrate, first synthesized in 1974 (Niemegeers et al., Arzneim. Forsch. 26:1551–1556 (1976)), is a piperidine derivative and a member of a series of potent fentanyl analogues. It is a powerful analgesic with an excellent safety margin as compared to other narcotic agents. It is furthermore characterized by a high selectivity and affinity (approximately 10 times greater than fentanyl) for “mu” opiate receptors. Sufentanil produces, unlike fentanyl or morphine, complete anesthesia with minimal side-effects. When compared with fentanyl, its pharmaco-kinetic profile in man shows a smaller volume of distribution, resulting in a terminal half-life intermediate between alfentanil and fentanyl. Sufentanil in high doses with 100% oxygen in patients undergoing major surgical procedures produces excellent cardiovascular stability and preserves cardiac output and myocardial oxygen balance with minimal changes in heart rate. Furthermore, sufentanil suppresses most hormonal responses to surgical stimulation without producing significant cardiovascular depression. Additionally, sufentanil, like fentanyl, does not cause histamine release. Also, in low to moderate doses, sufentanil may have further advantages over other narcotic agents. When compared with meperidine, morphine and fentanyl, in patients undergoing general surgery under balanced anesthesia, sufentanil provides stable cardiovascular parameters, low preoperative catecholamine plasma levels, very little need for additional inhalation supplementation, and a low incidence of postoperative respiratory depression.
Because of its remarkably low cardiovascular toxicity, sufentanil citrate has been evaluated as a total intravenous anesthetic for major surgical procedures. It is primarily used for open heart surgery and major operations in patients with severe cardiovascular compromise.
The chemical name for sufentanil is N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide. In its citrate form the chemical name is N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide, 2-hydroxy-1,2,3-propanetricarboxylate. The citrate form has an empirical formula of C28H38N2O9S. Sufentanil citrate is a white crystalline powder (molecular weight=578.68) with a reported melting point of 136.3° C., and is very soluble in water and most common organic solvents.
Synthesis of sufentanil is disclosed in U.S. Pat. No. 3,998,834 to Janssen. The process described therein, however, is quite lengthy and complicated. An improved synthesis is described in U.S. Pat. No. 5,489,689 to Mallinckrodt. The present invention is an improvement over the Janssen method and an alternative procedure to the procedure of the '689 patent.
While the 4-anilidopiperidine opioid analogues exemplified by fentanyl (1b) are readily
prepared, the 4-alkyl analogues such as Sufentanil (1a) and alfentanil (1c) have been more difficult. Alfentanil HCl is currently supplied by Janssen Pharmaceutical, Ltd. (Belgium). The Janssen syntheses of sufentanil and alfentanil proceed in 10 steps in low overall yield (˜2%) (Scheme I). Modifications have improved the yield in the conversion of nitrile 2 to ester 5. The Janssen synthesis commences with the condensation of N-benzyl-4-piperidone with aniline in the presence of potassium cyanide (the Strecker synthesis) to yield the cyanoamine 2. Sequential hydrolysis of cyanoamine 2 to anilino amide 3 (concentrated sulfuric acid) and then to the corresponding acid 4 was achieved with concentrated hydrochloric acid at reflux. Esterification of the acid 4 gave ester 5 which on reduction with lithium aluminum hydride gave 4-(hydroxymethyl)4-anilino-N-benzylpiperidine 6. The alcohol 6 was etherified (NaH, MeI, HMPA) to give the methyl ether 7 and then propionylated to give the amide 8. The amide was subjected to hydrogenolysis of the N-benzyl protecting group and the resulting secondary amine 9 was N-alkylated with either the thiophene side chain or the tetrazole side chain to generate sufentanil (shown in Scheme I) or alfentanil.

For large scale production, use of cyanide in the initial step is undesirable from a safety and environmental point of view. Another problem that complicates this scheme is the tendency of the secondary piperidines 9 to suffer an intramolecular acyl-group migration (Scheme II) upon standing (either neat or in solution) (Colapret et al., J. Med. Chem. 32:968 (1989)). The analogous O to N acyl migration has been well precedented.
